Serum IgG2 levels are specifically associated with whole-body insulin-mediated glucose disposal in non-diabetic offspring of type 2 diabetic individuals. a cross-sectional study

.Preclinical studies suggested that IgG2c isotype may specifically impair skeletal muscle insulin sensitivity in mice. In this study we investigated the association between serum levels of the four IgG subclasses and insulin sensitivity in non-diabetic individuals. Total IgG, IgG1, IgG2, IgG3 and IgG4 levels were measured in 262 subjects. Whole-body insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp. IgG2 levels were positively correlated with BMI, waist circumference, 2-h postload glucose levels and complement C3. Serum IgG2, but not IgG1, IgG3 and IgG4 levels were negatively correlated with whole-body insulin sensitivity (r = −0.17; P = 0.003) and muscle insulin sensitivity index (r = −0.16; P = 0.03) after adjustment for age and gender. No significant correlation was found between IgG2 levels and hepatic insulin resistance assessed by HOMA-IR and liver IR index. In a multivariable regression analysis including variables known to affect insulin sensitivity such as age, gender, BMI, smoking, lipids, inflammatory markers, fasting and 2-h post-load glucose levels, IgG2 levels were independently associated with insulin-stimulated glucose disposal (β = −0.115, 95% CI: −0.541 to −0.024; P = 0.03). These data demonstrate the independent association between higher levels of IgG2 and decreased whole-body insulin sensitivity, thus confirming in humans the animal-based evidence indicating the pathogenic role of IgG2 in insulin resistance

Adipocyte JAK2 Regulates Hepatic Insulin Sensitivity Independently of Body Composition, Liver Lipid Content, and Hepatic Insulin Signaling.

Disruption of hepatocyte growth hormone (GH) signaling through disruption of Jak2 (JAK2L) leads to fatty liver. Previously, we demonstrated that development of fatty liver depends on adipocyte GH signaling. We sought to determine the individual roles of hepatocyte and adipocyte Jak2 on whole-body and tissue insulin sensitivity and liver metabolism. On chow, JAK2L mice had hepatic steatosis and severe whole-body and hepatic insulin resistance. However, concomitant deletion of Jak2 in hepatocytes and adipocytes (JAK2LA) completely normalized insulin sensitivity while reducing liver lipid content. On high-fat diet, JAK2L mice had hepatic steatosis and insulin resistance despite protection from diet-induced obesity. JAK2LA mice had higher liver lipid content and no protection from obesity but retained exquisite hepatic insulin sensitivity. AKT activity was selectively attenuated in JAK2L adipose tissue, whereas hepatic insulin signaling remained intact despite profound hepatic insulin resistance. Therefore, JAK2 in adipose tissue is epistatic to liver with regard to insulin sensitivity and responsiveness, despite fatty liver and obesity. However, hepatocyte autonomous JAK2 signaling regulates liver lipid deposition under conditions of excess dietary fat. This work demonstrates how various tissues integrate JAK2 signals to regulate insulin/glucose and lipid metabolism

Effect of Progressive Weight Loss on Lactate Metabolism: A Randomized Controlled Trial.

OBJECTIVE:Lactate is an intermediate of glucose metabolism that has been implicated in the pathogenesis of insulin resistance. This study evaluated the relationship between glucose kinetics and plasma lactate concentration ([LAC]) before and after manipulating insulin sensitivity by progressive weight loss. METHODS:Forty people with obesity (BMI = 37.9 ± 4.3 kg/m2 ) were randomized to weight maintenance (n = 14) or weight loss (n = 19). Subjects were studied before and after 6 months of weight maintenance and before and after 5%, 11%, and 16% weight loss. A hyperinsulinemic-euglycemic clamp procedure in conjunction with [6,6-2 H2 ]glucose tracer infusion was used to assess glucose kinetics. RESULTS:At baseline, fasting [LAC] correlated positively with endogenous glucose production rate (r = 0.532; P = 0.001) and negatively with insulin sensitivity, assessed as the insulin-stimulated glucose disposal (r = -0.361; P = 0.04). Progressive (5% through 16%) weight loss caused a progressive decrease in fasting [LAC], and the decrease in fasting [LAC] after 5% weight loss was correlated with the decrease in endogenous glucose production (r = 0.654; P = 0.002) and the increase in insulin sensitivity (r = -0.595; P = 0.007). CONCLUSIONS:This study demonstrates the interrelationships among weight loss, hepatic and muscle glucose kinetics, insulin sensitivity, and [LAC], and it suggests that [LAC] can serve as an additional biomarker of glucose-related insulin resistance

Impaired glucose metabolism in subjects with the Williams-Beuren syndrome. A five-year follow-up cohort study

Objective. The Williams-Beuren syndrome (WS) is associated with impaired glucose metabolism (IGM) early in adulthood. However, the pathophysiology of IGM remains poorly defined, due to the lack longitudinal studies investigating the contribution of β-cell dysfunction and impaired insulin sensitivity. This study aimed at assessing incidence of IGM and the underlying mechanisms in WS adults. Methods. This observational, longitudinal (5-year), cohort study enrolled thirty-one consecutive WS subjects attending a tertiary referral center. An oral glucose tolerance test (OGTT) was performed yearly and used to classify patients as normal or IGM, including impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) and diabetes mellitus (DM), and to calculate surrogate measures of insulin secretion and/or sensitivity. Results. IGM patients were 18 (58.1%, three DM) at baseline and 19 (61.3%, five DM) at end-of-follow-up. However, 13 individuals changed category of glucose homeostasis in both directions during follow-up (8 progressors, 5 regressors) and 18 did not (8 non-progressors, 10 non-regressors). New cases of IGM and DM were 11.1 and 2.53 per 100 persons-year, respectively, and were treated non-pharmacologically. In the whole cohort and, to a higher extent, in progressors, indices of early-phase insulin secretion and insulin sensitivity decreased significantly from baseline to end-of-follow-up, with concurrent reduction of the oral disposition index and insulin secretion-sensitivity index-2 (ISSI-2), compensating insulin secretion for the level of insulin resistance. No baseline measure independently predicted progression, which correlated with change from baseline in ISSI-2. Compared with patients with normal glucose homeostasis, IGT subjects had impaired insulin sensitivity, whereas insulin secretion was reduced only in those with IFG+IGT or DM. Conclusions. IGM incidence is high in young adults with WS, suggesting the need of early screening and timed intervention. As in classical type 2 diabetes, impaired insulin sensitivity and β-cell dysfunction contribute, in this sequence, to progression to IGM and DM

FAM13A and POM121C are candidate genes for fasting insulin: functional follow-up analysis of a genome-wide association study

Aims/hypothesis: By genome-wide association meta-analysis, 17 genetic loci associated with fasting serum insulin (FSI), a marker of systemic insulin resistance, have been identified. To define potential culprit genes in these loci, in a cross-sectional study we analysed white adipose tissue (WAT) expression of 120 genes in these loci in relation to systemic and adipose tissue variables, and functionally evaluated genes demonstrating genotype-specific expression in WAT (eQTLs). Methods: Abdominal subcutaneous adipose tissue biopsies were obtained from 114 women. Basal lipolytic activity was measured as glycerol release from adipose tissue explants. Adipocytes were isolated and insulin-stimulated incorporation of radiolabelled glucose into lipids was used to quantify adipocyte insulin sensitivity. Small interfering RNA-mediated knockout in human mesenchymal stem cells was used for functional evaluation of genes. Results: Adipose expression of 48 of the studied candidate genes associated significantly with FSI, whereas expression of 24, 17 and 2 genes, respectively, associated with adipocyte insulin sensitivity, lipolysis and/or WAT morphology (i.e. fat cell size relative to total body fat mass). Four genetic loci contained eQTLs. In one chromosome 4 locus (rs3822072), the FSI-increasing allele associated with lower FAM13A expression and FAM13A expression associated with a beneficial metabolic profile including decreased WAT lipolysis (regression coefficient, R = −0.50, p = 5.6 × 10−7). Knockdown of FAM13A increased lipolysis by ~1.5- fold and the expression of LIPE (encoding hormone-sensitive lipase, a rate-limiting enzyme in lipolysis). At the chromosome 7 locus (rs1167800), the FSI-increasing allele associated with lower POM121C expression. Consistent with an insulin-sensitising function, POM121C expression associated with systemic insulin sensitivity (R = −0.22, p = 2.0 × 10−2), adipocyte insulin sensitivity (R = 0.28, p = 3.4 × 10−3) and adipose hyperplasia (R = −0.29, p = 2.6 × 10−2). POM121C knockdown decreased expression of all adipocyte-specific markers by 25–50%, suggesting that POM121C is necessary for adipogenesis. Conclusions/interpretation: Gene expression and adipocyte functional studies support the notion that FAM13A and POM121C control adipocyte lipolysis and adipogenesis, respectively, and might thereby be involved in genetic control of systemic insulin sensitivity

Enhanced insulin sensitivity associated with provision of mono and polyunsaturated fatty acids in skeletal muscle cells involves counter modulation of PP2A

International audienceAims/Hypothesis: Reduced skeletal muscle insulin sensitivity is a feature associated with sustained exposure to excess saturated fatty acids (SFA), whereas mono and polyunsaturated fatty acids (MUFA and PUFA) not only improve insulin sensitivity but blunt SFA-induced insulin resistance. The mechanisms by which MUFAs and PUFAs institute these favourable changes remain unclear, but may involve stimulating insulin signalling by counter-modulation/repression of protein phosphatase 2A (PP2A). This study investigated the effects of oleic acid (OA; a MUFA), linoleic acid (LOA; a PUFA) and palmitate (PA; a SFA) in cultured myotubes and determined whether changes in insulin signalling can be attributed to PP2A regulation. Principal Findings: We treated cultured skeletal myotubes with unsaturated and saturated fatty acids and evaluated insulin signalling, phosphorylation and methylation status of the catalytic subunit of PP2A. Unlike PA, sustained incubation of rat or human myotubes with OA or LOA significantly enhanced Akt-and ERK1/2-directed insulin signalling. This was not due to heightened upstream IRS1 or PI3K signalling nor to changes in expression of proteins involved in proximal insulin signalling, but was associated with reduced dephosphorylation/inactivation of Akt and ERK1/2. Consistent with this, PA reduced PP2Ac demethylation and tyrosine 307 phosphorylation-events associated with PP2A activation. In contrast, OA and LOA strongly opposed these PA-induced changes in PP2Ac thus exerting a repressive effect on PP2A.Conclusions/Interpretation: Beneficial gains in insulin sensitivity and the ability of unsaturated fatty acids to oppose palmitate-induced insulin resistance in muscle cells may partly be accounted for by counter-modulation of PP2A

Urocortin 2 Gene Transfer Improves Glycemic Control and Reduces Retinopathy and Mortality in Murine Insulin Deficiency.

Type 1 diabetes affects 20 million patients worldwide. Insulin is the primary and commonly the sole therapy for type 1 diabetes. However, only a minority of patients attain the targeted glucose control and reduced adverse events. We tested urocortin 2 gene transfer as single-agent therapy for insulin deficiency using two mouse models. Urocortin 2 gene transfer reduced blood glucose for months after a single intravenous injection, through increased skeletal muscle insulin sensitivity, increased insulin release in response to glucose stimulation, and increased plasma insulin levels before and during euglycemic clamp. The combined increases in both insulin availability and sensitivity resulted in improved glycemic indices-events that were not anticipated in these insulin-deficient models. In addition, urocortin 2 gene transfer reduced ocular manifestations of long-standing insulin deficiency such as vascular leak and improved retinal function. Finally, mortality was reduced by urocortin 2 gene transfer. The mechanisms for these beneficial effects included increased activities of AMP-activated protein kinase and Akt (protein kinase B) in skeletal muscle, increased skeletal muscle glucose uptake, and increased insulin release. These data suggest that urocortin 2 gene transfer may be a viable therapy for new onset type 1 diabetes and might reduce insulin needs in later stage disease

Improved insulin sensitivity following a short-term whole body vibration intervention

Background and Objective: Despite being recommended for reducing the risk of type 2 diabetes (T2D) the majority of the population do not partake in the advised amount of regular exercise. While high intensity type training has been shown to produce improvements in insulin sensitivity its uptake in high risk populations has been questioned. Contrastingly, whole body vibration training (WBVT) is reported to benefit a range of outcomes in a variety of populations. Limited data exists regarding this training modality on insulin sensitivity. Current study assessed the effect of WBVT on oral glucose tolerance response. Method: Following institutional ethics approval, five young healthy sedentary individuals undertook oral glucose tolerance test (OGTT) prior to and on completion of 5-week progressive WBVT. Result: There were no changes in fasting plasma glucose concentrations before and after the 6 weeks of WBVT. Both pre- and post-training OGTT revealed no significant changes in plasma glucose concentrations over time. There was a 9% reduction in plasma glucose area under the curve (AUC) post training. The Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) decreased by 21% and Cederholm index of insulin sensitivity was increased by 18% following WBVT. Conclusion: Results suggest WBVT is associated with improved insulin sensitivity and could produce clinically relevant effects on fat metabolism in sedentary young people. Large-scale studies are now necessary to assess the effectiveness of WBVT in diabetic populations